Promise of monthly oral pill sparks renewed interest in post-exposure prophylaxis (PEP)

An unexpected but welcome development at the 26th International AIDS Conference (AIDS 2026) in Rio was the reappearance of post-exposure prophylaxis (PEP) for HIV as a subject for scientific study and funding.

PEP involves taking an antiretroviral drug or regimen as soon as possible after an exposure to HIV to stop it turning into an infection, whereas pre-exposure prophylaxis (PrEP) involves taking it in advance of a possible exposure. See aidsmap’s summary for more information.

PEP is the oldest drug-based HIV prevention method, dating back to the late 1980s, when zidovudine (AZT) was recommended for healthcare staff who may have been exposed to HIV at work – what’s known as occupational exposure. By the early 2000s, two- or three-drug regimens were recommended, usually based on standard oral PrEP (tenofovir / emtricitabine) plus a third agent.

But the two most basic features of PEP have remained and are enshrined in the World Health Organization’s guidelines, which are followed by most countries. Firstly, PEP should be taken ideally within 24 hours and certainly no more than 72 hours after an exposure. Secondly, it should consist of a four-week course. This was thought necessary for situations where PEP was started late and HIV may have gained a foothold inside cells.

There is general agreement on the 24 to 72 hour time window. But it has been acknowledged for some time in the era of event-driven PrEP, which deems a three-day course of two drugs sufficient to prevent HIV transmission via anal sex, that a four-week course of three drugs is probably far in excess of what is necessary, risks side effects, and is a challenge both to starting PEP and to adhering to it. One meta-analysis found only 57% of people taking PEP completed the course, though adherence was better to a three-drug combination pill.

Dr Sinead Delany-Moretlwe of the University of the Witwatersrand in South Africa, introducing a session on PEP at AIDS 2026, remarked that these barriers had left PEP untapped. Because little data on PEP's efficacy or effectiveness in humans exists, regulatory agencies have never licensed a drug for it, and it is always prescribed off-label. But with longer-acting drugs potentially coming onto the market soon, PEP could in theory become a one-off measure. Delany-Moretlwe highlighted young women and adolescent girls, along with sexual assault survivors, as potential beneficiaries if it were stocked and provided at appropriate venues such as emergency rooms, rape crisis centres, pharmacies and community centres.

“Even at vending machines,” she added – a reference to São Paulo’s scheme of PEP and PrEP vending machines at metro stations, which Adriano Queiroz da Silva of the city’s department of public health had presented at a pre-conference meeting on prevention. Although 92% of users were men, among the 8% who were women, 70% were seeking PEP, not PrEP.

What has really renewed interest in PEP is that by late 2027 we will probably have a pill ideal for it – alimatravir or MK-8527, a one-pill, once-a-month antiretroviral, that is being developed for PrEP. Its developers, Merck, announced just before the conference that they were entering into licensing agreements with seven generic manufacturers and 129 countries even in advance of full enrolment to its phase III EXPrESSIVE 10 and, EXPrESSIVE 11 studies, in order to scale up provision as fast as possible.

For PrEP, alimatravir will be ready for use immediately upon licensing. But for PEP, the lack of clinical data will still hold it back. For this reason, a PEP summit was held in Johannesburg in May this year where 54 researchers, regulators, and community and pharma representatives focused on how to generate evidence on the efficacy of PEP.

The problem in simplifying PEP lies in devising a study to prove it would work. PEP is an emergency measure. A placebo-controlled study – comparing PEP with doing nothing – would not be ethical, while comparing single-dose PEP with the standard four-week regimen may not be ethical either, as this would be comparing something which might not work with something which we know can work. It would also be unfeasibly large – modelling suggests about 12,500 people for a two-year study.

Four trial designs to get round these obstacles were considered at the summit.

Counterfactual placebo. Participants would be randomised to alimatravir or standard PrEP, but not to placebo. Instead, the likelihood of HIV infection from unprotected exposures would be mathematically modelled. This is similar to the structure of the PURPOSE PrEP studies. Having a modelled placebo arm reduces the number required by 70%, but even so, some 4000 people at significant HIV risk, would be required – and told not to switch to PrEP during the study.

Pragmatic trial. This would simply compare the efficacy of single-dose PrEP versus the 28-day regimen in three populations: gay and bisexual men, female sexual assault survivors, and occupational exposures. It would not seek to establish absolute biological efficacy, but by comparing the near 100% ‘adherence’ of a single monthly pill with adherence to a 28-day regimen, it would assume superior efficacy on the basis of adherence. Alternatively, the method of PrEP used could be staggered in time so that each cohort uses one method for a certain time and then the other. This is similar to the design of the PROUD PrEP trial. However, this design would be open to skewed results if people changed behaviour over time.

Preference trial. This would offer people the choice of whether to be randomised to single-pill or 28-day PrEP or, if they did not want to be randomised, they could still receive their choice of regimen. This is like the study of the Moderna COVID vaccine, where some participants were randomised to vaccine or placebo, while others chose to receive the vaccine open-label. If, however, most people chose non-randomisation, if would end up as a very large trial anyway, and is better suited to a follow-on open-label study where everyone has a choice of regimen and knows what they are taking.

Zero-event trial. This was the design that the PEP summit eventually agreed on and which will be recommended. It gets round the problem of the rarity of exposures and the greater rarity of infections despite PEP by turning the normal practice on its head. Instead of comparing the number of events, it looks at how long it takes for a single event – an HIV infection despite PEP – to occur. It would track what happened each time someone was issued PEP after an exposure, so that by the time a PEP failure occurred, there would be plenty of data to find out how it differed from the instances where infection did not occur. This study design also lends itself to ‘PEP in pocket’, where people are given their own supply of pills to use after an exposure and have annual follow-up. Statistically, modellers estimate that it might only take a study involving 1,000 people to establish a difference between PEP regimens.

The Gates Foundation supported the PEP summit and have pledged to help with the study as part of their strategy. The Foundation’s Max Lataillade said that they were aiming to help establish ideal ‘target product profiles’ (TPPs) for HIV treatment, PrEP and PEP. Their ideal TPP for treatment would be an effective two-drug combination pill that could be dosed weekly (an example would be islatravir / lenacapavir) or ideally monthly, or an injectable two-drug combination that could be given every six months to a year (we need a companion drug to lenacapavir, and they are being studied). For PrEP we already have a twice-yearly injection and may soon have a monthly pill. And for PEP, if alimatravir proves effective, that may be single-pill protection.

Adaobe Olisa, of the Nigerian NGO Root to Rise, welcomed the possibility of single-dose PEP, but noted that only 36 countries have PEP guidelines, only two of those allow community access to PEP, and there is no data on global PEP use.

“Still”, she remarked, “When there is no data, that’s when the community finds its own.” Twenty-eight community respondents from 13 countries in three regions answered a survey which showed that lack of awareness of PEP, stigma and fear of public exposure were the biggest barriers to its use. Eighty-two per cent of respondents said that communities would definitely use short-course PEP as a prevention choice if it became available and 100% said they probably would.

If trials show alimatravir works as PEP, Adaobe Olisa concluded, “This is where the question shifts from ‘Does it work?’ to ‘Can we deliver it sustainably, safely and equitably at scale?’”